Synthesis, reactions and antimicrobial activity of thieno[2,3-c]pyridazine derivatives

Article abstract of DOI:10.3184/030823409X12508790019612

The reaction of N¹-(un)substituted 4-aminosulfonamide with 6-chloropyridothienopyridazine (5) and 8-chloropyrimidothienopyridazine (14) gave 6-substituted aminopyridothienopyridazine (9) and 8-substituted aminopyrimidothienopyridazine (16) resp

Full text of DOI:10.3184/030823409X12508790019612

JOURNAL OF CHEMICAL RESEARCH 2009
OCTOBER, 593–598
RESEARCH PAPER 593
Synthesis, reactions and antimicrobial activity of thieno[2,3-c]pyridazine
derivatives
Fatma El Mariah*
Department of Chemistry, Faculty of Girls, Ain Shams University, Cairo, Egypt
The reaction of N1-(un)substituted 4-aminosulfonamide with 6-chloropyridothienopyridazine (5) and 8-chloro-
pyrimidothienopyridazine (14) gave 6-substituted aminopyridothienopyridazine (9) and 8-substituted amino-
pyrimidothienopyridazine (16) respectively. All of the derivatives have been characterised by analytical and
spectroscopic studies and also tested for their in vitro antibacterial and antifungal activity against a variety of
microorganisms.
Keywords: 6-substituted aminopyridothienopyridazine, 8-substituted pyrimidothienopyridazine, antimicrobial activity
The pyridazine1 ring is a recurrent structural component
Cl
of biologically active compounds.2 Moreover, pyridazines
O
Ph
N
Ph
N
NH
are useful intermediates in the construction of several
other heterocycles3 and in physical organic chemistry.4
Recently they have been explored as new a-helix mimetics.5
On the other hand, thienopyridazines have also attracted
attention because of their promising biological activities.6,7
In connection with these facts, the utility of substituted
thieno[2, 3-c]pyridazines as a synthon for the preparation of
new substituted pyrido[2', 3':4, 5]thieno[2, 3-c]pyridazines
and pyrimido[4', 5':4, 5]thieno-[2, 3-c]pyridazine is reported
and an analysis of their biological activity is described.
Amino ketone and aminocyano serve as good synthons for
formation of a pyridine and pyrimidine rings.3
The precursor, 5-amino-6-benzoyl-3, 4-diphenylthieno
[2, 3-c]pyridazine (1), was prepared from 4-cyano-5, 6-diphenyl-
pyridazine-3(2H)thione and w-chloroacetophenone using
excess potassium carbonate in refluxing acetone.1
Chloroacetylation of (1) with chloroacetyl chloride gave the
5-chloroacetyl-amino (2) which was obtained in analytically
pure form directly from the reaction mixture in 85% yield.8
The reaction of a 1:1 mixture of compound (2) and sodium
cyanide in ethanol afforded a solid for which the theoretically
possible structure (3) was eliminated based on microanalytical
and spectroscopic data. These data can only be intelligibly
interpreted in terms of structure (4) (Scheme 1).
NH2
Ph
Ph
Ph
O
Ph ClCH2COCl
Benzene, pyridine, r.t.
N
N
S
S
O
2
1
NaCN, EtOH
reflux
CN
O
O
Ph
HN
Ph
Ph
NH
Ph
CN
Ph
N
N
S
4
Ph
N
S
O
N
3
Cl
Ph
N
Ph
POCl3
Reflux
CN
N
N
S
Ph
5
Scheme 1
The structure of (4) is substantiated from micro analytical data
1
and was confirmed by IR, H NMR, and mass spectroscopy.
piperidine, and morpholine reacted with (5) in refluxing
benzene to furnish 6-substituted aminopyridothienopyridazine
derivatives (7) and (8a–d) respectively.
Its IR spectrum revealed the absence of benzoyl ketone group
in addition to the presence of 3423, 1602 (NH), 2339 (C≡N),
1679 (cyclic, C=O) cm-1, molecular ion peak at m/z = 457 and
1H NMR d ppm: 7.2–7.82 (m, 15H, 3Ph), 8.10 (s, 1H, NH), as
well as the disappearance of the methylene group.
The formation of (4) is assumed to proceed via the formation
of the intermediate (3) which underwent smooth cyclisation to
the corresponding fused pyridothienopyridazine.
Moreover independent chemical proof for compound (4)
seemed necessary. Thus, the reaction of 7-cyano-3, 4, 8-
triphenylpyrido[2', 3':4, 5]thieno[2, 3-c]pyridazin-6(5H)-one
(4) with phosphorus oxy-chloride afforded the oxygen free
compound which was identified to be the chloro derivative (5).
The chlorine atom of compound (5) showed the expected
reactivity towards nucleophilic reagents. Treatment of 6-chloro
derivative (5) with various nucleophiles such as alkoxide ions,
amines and hydrazine led to normal halide displacement to the
other 6-substituted derivatives (Scheme 2).
The investigations were extended to include the behaviour of
(5) towards aromatic amines containing sulfonamide moiety in
the para positions for antimicrobial screening. Thus, treatment
of (5) with N1-(un) substituted 4-aminobenzenesulfonamides
under reflux in benzene yielded the corresponding 6-
substituted aminopyridothienopyridazines (9a–f) (Scheme 2).
The structure of the synthesised compounds was established
on the basis of their IR, mass and 1H NMR spectral studies.
To expand the use of chloro derivative (5), when reacted
with ethanolic thiouronium salt in 85% yield was obtained
which, on hydrolysis with 2.5 N sodium hydroxide followed
by acidification with hydrochloric acid (pH 6), gave 7-cyano-
3, 4, 8-triphenylpyrido[2', 3':4, 5]thieno[2, 3-c]pyridazine-
6(5H)-thione (10).The structure of (10) was determined from
micro analytical and spectroscopic data.
Furthermore, treatment of (5) with hydrazine hydrate
in refluxing ethanol resulted in the formation of novel
aminopyrazolopyridothienopyridazine derivative (11) in
high yield. The structure of (11) was established on the
basis of analytical and spectral data. Its IR spectrum
revealed the absence of cyano group and the presence of
amino group. Also, the mass spectrum showed a molecular ion
The reaction of compound (5) with alkoxide such as sodium
methoxide and or sodium ethoxide afforded 6-methoxy (6a)
and 6-ethoxy (6b) derivatives respectively. Moreover aniline
and secondary amines such as diethyl amine, pyrrolidine,
* Correspondent. E-mail: fatma_elmariah@yahoo.com

594 JOURNAL OF CHEMICAL RESEARCH 2009
O
S
HN
NHR
Ph
N
O
Ph
CN
N
N
S
9a-f
Ph
9a, R= H
b, R= n-Pr
c, R= Bn
d, R= C6H4Me (p-)
e, R= C6H4OMe (p-)
f, R= C6H4NO2 (p-)
OR
Ph
NHPh
CN
Ph
Ph
N
N
Ph
Ph
RONa
CN
PhNH2
5
ROH
N
N
N
S
N
S
7
Ph
2o amine
6a,b
6a, R= Me
b, R= Et
R
Ph
N
Ph
CN
N
N
S
Ph
8a-d
8a, R= diethylamino
b, R= pyrrolidino
c, R= piperidino
d, R= morpholino
Scheme 2
peak at m/z = 472. The formation of (11) is assumed to
proceed via the formation of intermediate followed by
intramolecular cyclisation of amino group to the cyano group
(Scheme 3).
In the second track study, the pyrimido[4', 5':4, 5]thieno
[2, 3-c]pyridazine derivative (13) was prepared according to
previously described procedure.9,10 Starting from 5-amino-3,
4-diphenylthieno[2, 3-c]pyridazine-6-carboxamide (12) and
formamide or formic acid. Upon treatment with phosphorus
oxychloride, (13) afforded the 8-chloro derivative (14),10
which exhibited a remarkable reactivity of its 8-chloro
substituent towards nucleophilic agents, thus affording
the new 8-substituted pyrimido[4', 5':4, 5]-thieno[2, 3-c]
pyridazine derivatives (16a–g) and (17a,b) (Scheme 4).
The N1-(un)substituted 4-aminobenzenesulfonamides (15)
were prepared using a previously described method.7,11 The
nucleophilic substitution of the 8-chloro group of compound
(14) yielded the corresponding 8-substituted aminopyrimido
[4', 5':4, 5]thieno-[2, 3-c]pyridazine derivatives (16a–g) and
(17a,b). The structure of the synthesised compounds was
established on the basis of their IR, MS and 1H NMR spectral
studies. Compound (16) and (17) showed a characteristic
singlet between d 7.36 ppm and d 9.86 ppm for H-6 in the
1H NMR spectra.
NH
S
NHNH2
Ph
Ph
N
NH2
CN
N
S
Ph
Ph
CN
H2N
NH2
NH2NH2.H2O
5
N
N
EtOH
EtOH
N
S
N
S
Ph
Ph
1) NaOH/H2O
2) HCl
H
N
S
Ph
N
Ph
N
HN
N
Ph
CN
Ph
NH2
N
N
N
S
Ph
Ph
S
10
11
Scheme 3

JOURNAL OF CHEMICAL RESEARCH 2009 595
Ph
N
Ph
N
NH2
NH
O
Ph
Ph
NH2
O
HCONH2 or HCOOH
reflux 14h
N
S
N
N
S
13
12
POCl3 / PCl5
reflux 7h
O
S
O
Ph
N
N
N
H2N
NHR
Ph
Ph
N
Ph
15a-g
N
N
O
S
Cl
S
N
N
S
HN
NHR
14
O
16a-g
2o amine
15, 16 a, R= H
b, R= n-Pr
c, R= CH2Ph
d, R= Ph
e, R= C6H4OMe (p-)
f, R= C6H4Cl (p-)
g, R= C6H4NO2 (p-)
Ph
N
N
S
N
Ph
N
R
17a,b
17 a, R= N(C2H5)2
b, R= Pyrrolidino
Scheme 4
Screening for antimicrobial activities
against the both examined fungi Candida albicans and
Aspergillus niger (compounds 5, 6a, 6b, 8a, 8b, 9c and 11).
In addition, compound 10 showed very high antifungal
activity against one of examined fungi.
It should be mentioned here that three compounds (5, 6b
and 9f) showed very high, high or moderate antimicrobial
activity against all examined bacteria and fungi.
In conclusion, results of antimicrobial activity revealed
that synthesised compounds showed high and/or very high
antimicrobial activity against bacteria and fungi respectively.
It could be concluded from these results that the biologically
active compounds are nearly as active as standard antibacteria
Ciprofloxacin against the tested both Gram positive bacteria
Staphylococcus aureus and Bacillus subtilis and Gram negative
bacteria Escherichia coli and Pseudomonas aeruginosa.
On the other hand, the biologically active of synthesised
compounds are active as standard Fungicide Nystin against
the both tested fungi Candida albicans and Aspergillus niger.
Applying the agar plate diffusion technique12 the newly
synthesised compounds were screened in vitro for antimicrobial
activity against Gram positive bacteria (Staphylococcus aureus,
Bacillus subtilis), Gram negative bacteria (Escherichia coli,
Pseudomonas aeruginosa), yeast (Candida albicans) and fungi
(Aspergillus niger). In this method a standard 5 mm sterilised
filter paper disc impregnated with the compound (0.3 mg/
0.1 mL of dimethyl formamide) was placed on an agar plate
seeded with the test organism. The plates were incubated for
24 h at 37°C for bacteria and 28°C for fungi. The inhibition
zone of bacterial and fungal growth around the disc was
determined. The screening results are given in (Table 1).
The antimicrobial activity of the compounds against
examined Gram positive bacteria Staphylococcus aureus
and Bacillus subtilis varied from one compound to another.
Six synthesised compounds showed high antimicrobial
activity against one or both Gram positive examined bacteria
Staphylococcus aureus (compounds 5, 6a, 6b, 9b, 9c and
9f) and/or Bacillus subtilis (compounds 6a, 9b, 9f and 16f),
whereas16compoundsshowedmoderateantimicrobialactivity
against one/or both examined Gram positive bacteria. On the
other hand, 15 compounds showed moderate antimicrobial
activity against one or both examined gram negative bacteria
Escherichia coli and/or Pseudomonas aeruginosa. Only four
synthesised compounds showed antimicrobial activity against
both Gram negative examined bacteria (compounds 5, 6b,
9b and 9f). It is clear from this results that four compounds
showed high or moderate antibacterial activity against both
Gram positive and Gram negative bacteria (compound 5, 6b,
9b and 9f).
Experimental
Melting points were determined in open glass capillaries and are
uncorrected. Elemental analyses were carried out in the micro
analytical laboratory of the Faculty of Science, Cairo University.
The IR spectra of compounds were recorded on a Perkin-Elmer
spectrophotometer model 1430 as potassium bromide pellets and
frequencies are reported in cm-1. The 1H NMR spectra were recorded
on a Perkin-Elmer R12B spectrometer 200 MHz and chemical shifts
d are in ppm relative to internal TMS, and mass spectra were recorded
on a mass spectrometer HP model MS 5988 El 70ev. Reactions were
routinely followed by thin layer chromatography (TLC) on silica
gel; F254 aluminum sheets (Merck). The spots were detected by
UV irradiation at 254–365 nm.
Furthermore, (6b) and (11) synthesised compounds showed
very high antifungal activity against both examined fungi
Candida albicans (yeast) and Aspergillus niger. Only seven
compounds showed very high or high antifungal activity
Compounds (1, 2, 12, 13, 14 and 15) were prepared by the reported
methods.7,8,9,10,11
7-Cyano-3,4,8-triphenylpyrido[2',3' : 4,5]thieno[2,3-c]pyridazin-
6(5H)-one (4): To a solution of compound (2) (0.48 g, 1.0 mmol) in

596ꢀ JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2009
Table 1 Antibacterial and antifungal activity
Sample no.
Staphylococcus
aureus
Bacillus
subtilis
Escherichia
coli
Pseudomonas
aeruginosa
Candida
albicans
Aspergillus
niger
4
-
+ +
+ +
+ + +
+ +
-
+ +
+ +
+ +
-
+ +
-
+ + + +
+ + + +
+ + +
+ + + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + + +
+ + + +
+ + +
+ + +
+ + + +
+ + + +
-
+ +
+ + +
+ + +
+ + + +
+ + +
+ + + +
+ +
5
+ + +
+ + +
+ + +
+ +
+ +
+ +
-
+ +
+ +
6a
+ +
-
6b
+ +
+ +
8a
+ +
-
8b
+ +
-
8c
+ +
-
8d
-
-
-
9a
-
-
-
+ +
-
+ + +
-
9b
+ + +
+ + +
+ +
+ +
+ + +
+ +
+ +
+
+ + +
+ +
+ +
+ +
+ + +
+ +
+
+ +
+ +
9c
-
-
9d
-
+ +
9e
+ +
-
-
9f
+ +
+ +
+ +
10
+ +
-
+
-
11
+ +
+ + + +
+ +
+ +
+ +
16a
-
-
-
+ +
16b
+ +
-
+ +
+
+
+
+ +
+ +
+ + + +
_
+
-
-
16c
-
-
-
-
16d
+ +
-
+ +
-
+ +
+ + +
+ +
16e
-
-
-
16f
+ + +
+
-
-
+ + + +
_
-
-
+ + +
-
-
-
+ +
16g
-
-
+
17a
-
-
+ +
17b
-
-
+ +
Ciprofloxacin
Fungicide Nystin
+ + + +
_
+ + + +
_
-
-
+ + + +
+ + + +
The concentration of all synthesised compounds and two references compounds was 0.30 mg/0.10 mL of dimethyl formamide.
Zone of inhibition: + = < 15 mm; + + = 15 – 24 mm; + + + = 25 – 34 mm; + + + + = 35 – 44 mm; – = no inhibition.
ethanolꢀ(20ꢀmL),ꢀsodiumꢀcyanideꢀ(0.074ꢀg,ꢀ1.5ꢀmmol)ꢀwasꢀadded.ꢀ
The reaction mixture was heated under reflux for 3 h, and then the
solventꢀwasꢀconcentrated.ꢀTheꢀsolidꢀproductꢀwasꢀcollected,ꢀdriedꢀandꢀ
recrystallised from ethanol to give 0.35 g (73%) of 4ꢀasꢀredꢀcrystals,ꢀ
m.p.ꢀ 164–165ꢀ°C;ꢀ IR(cm-1): 3423, 1602 (NH), 2339 (C≡N), 1679
(cyclicꢀC=O)ꢀcm-1;ꢀMSꢀ(m/z%): 457 (M+, 4), 431 (4), 403 (6), 326
6-Substitutedꢀ aminopyridothienopyridazineꢀ derivativesꢀ (7) and
(8a-d); generalꢀprocedure
A mixture of 6-chloro-7-cyano-3, 4, 8-triphenylpyrido[2', 3':4, 5]ꢀ
thieno[2, 3-c]pyridazine (5)ꢀ(1.0ꢀmmol)ꢀaniline,ꢀandꢀtheꢀsecondaryꢀ
amines,ꢀnamelyꢀdiethylꢀamine,ꢀpyrrolidine,ꢀpiperidineꢀandꢀmorpho-
line respectively (1.0 mmol) were refluxed in benzene (20 mL)ꢀ
for 5 h, then the solvent was concentrated. The solid productꢀ
was collected, dried and recrystallised from benzene to give (7)ꢀandꢀ
(8a–d).
1
(8), 286 (7), 226 (100), 231 (5), 171 (6), 93 (17), 81 (14); HꢀNMRꢀ
(DMSOꢀ–ꢀd6)ꢀd ppm: 7.20–7.82 (m, 15H, 3Ph), 8.1 (s, 1H, NH). Anal.
Calcd for C28H16N4OS: C, 73.66; H, 3.53; N, 12.27. Found: C, 73.40;
H, 3.60; N, 12.50%.
6-Anilino-7-cyano-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thieno[2,3-c]ꢀ
pyridazine (7): Yield (0.49 g, 92%), m.p. 148–150°C; IR(cm-1): 3387
(NH), 2126 (C≡N), 1583 (C=N) cm-1;ꢀMSꢀ(m/z%): 533 (M+ꢀ+ꢀ1,ꢀ11),ꢀ
446 (18), 414 (13), 275 (21), 169 (28), 128 (15), 92 (100), 77 (25); 1Hꢀ
NMRꢀ(DMSOꢀ–ꢀd6)ꢀd ppm: 3.98 (s, 1H, NH), 6.63–7.07 (m, 5H, Ph-
N), 7.14–7.95 (m, 15H, 3Ph). Anal. Calcd for C34H21N5S:ꢀC,ꢀ76.81;ꢀ
H, 3.98; N, 13.18. Found: C, 76.60; H, 4.10; N, 12.90%.
7-Cyano-6-diethylamino-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thienoꢀ
[2,3-c]pyridazineꢀ (8a): Yield (0.46 g, 90%), m.p. 96–97°C;ꢀ
IR(cm-1):2228(C≡N),1661(C=N),1341(3°-amine)cm-1;ꢀMSꢀ(m/z%):ꢀ
511ꢀ(M+, 3), 408 (11), 375 (10), 286 (7), 225 (5), 77 (100), 72 (34);ꢀ
1HꢀNMRꢀ(DMSOꢀ–ꢀd6)ꢀd ppm: 1.16 (t, 3H, CH3), 3.52 (q, 2H, CH2),ꢀ
7.27–7.92 (m, 15H, 3Ph). Anal. Calcd for C32H25N5S:ꢀC,ꢀ75.12;ꢀH,ꢀ
4.93; N, 13.69. Found: C, 75.40; H, 4.80; N, 13.90%.
7-Cyano-6-pyrrolidino-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thienoꢀ
[2,3-c]pyridazineꢀ (8b):ꢀ Yield (0.43 g, 85%), m.p. 146–147°C;ꢀ
IR(cm-1): 2218 (C≡N), 1634 (C=N), 1339 (3°-amine) cm-1;ꢀ MSꢀ
(m/z%): 509 (M+, 2), 483 (8), 363 (28), 286 (3), 134 (12), 101 (8),
89 (100). Anal. Calcd for C32H23N5S: C, 75.42; H, 4.55; N, 13.74.
Found: C, 75.70; H, 4.70; N, 13.50%.
7-Cyano-6-piperidino-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thienoꢀ
[2,3-c]pyridazineꢀ (8c):ꢀ Yield (0.42 g, 80%), m.p. 117–118°C;ꢀ
IR(cm-1):2229(C≡N),1660(C=N),1378(3°-amine)cm-1;ꢀMSꢀ(m/z%):ꢀ
523 (M+, 8), 408(11), 375 (39), 300 (5), 237 (2), 84 (100). Anal.
Calcd for C33H25N5S: C, 75.69; H, 4.81; N, 13.38. Found: C, 75.40;
H, 4.90; N, 13.10%.
6-Chloro-7-cyano-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thieno[2,3-c]ꢀ
pyridazineꢀ(5):Amixtureof7-cyano-3, 4, 8-triphenylpyrido[2',3':4, 5]ꢀ
thieno[2, 3-c] pyridazin-6(5H)-one (4)ꢀ(0.46ꢀg,ꢀ1.0ꢀmmol)ꢀinꢀexcessꢀ
phosphorus oxychloride (20 mL) was heated for 5 h. The excess
phosphorusꢀoxychlorideꢀwasꢀevaporatedꢀunderꢀreducedꢀpressure,ꢀice-
cold water was added. The separated solid product was filtered off,
washed with water, dried and recrystallised from ethanol to give 0.38
g (83%) of 5 as pale brown crystals, m.p. 152–153°C. IR(cm-1):ꢀ2229ꢀ
(C≡N), 1599 (C=N) cm-1;ꢀMSꢀ(m/z%): 475 (M+, 3), 477(M+ꢀ+ꢀ2,ꢀ5),ꢀ
394 (4), 368 (6), 286 (6), 185 (15), 109 (18), 96 (51), 89 (5), 84 (40),
77 (36), 57 (100). Anal. Calcd for C28H15ClN4S: C, 70.80; H, 3.18;
N, 11.80. Found: C, 71.10; H, 3.30; N, 11.50%.
6-Substitutedꢀderivatives 6a, b;ꢀgeneralꢀprocedure
A mixture of 6-chloro-7-cyano-3, 4, 8-triphenylpyrido[2', 3':4, 5]ꢀ
thieno[2, 3-c]pyridazine (5)ꢀ(1.0ꢀmmol) and sodiumꢀmetalꢀ(1.5ꢀmmol)ꢀ
in dry methanol, absolute ethanol (10 mL) respectively was refluxed
for 3 h. The excess solvent was evaporated and water was added. The
separated solid product was filtered off, washed with water, dried and
recrystallised from ethanol to give (6a, b)ꢀrespectively.
7-Cyano-6-methoxy-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thieno[2,3-c]ꢀ
pyridazine (6a): Yield (0.38 g, 81%), m.p. 158–159°C; IR(cm-1):ꢀ
2193 (C≡N), 1593 (C=N) cm-1;ꢀMSꢀ(m/z%): 470 (M+, 0.2), 393 (0.6),
286 (1), 184 (0.70), 139 (11), 127 (11), 101(6), 95 (29), 89 (8), 77
(49), 69 (54), 57(100). Anal. Calcd for C29H18N4OS:ꢀC,ꢀ74.02;ꢀH,ꢀ
3.86; N, 11.91. Found: C, 74.30; H, 4.00; N, 11.70%.
7-Cyano-6-ethoxy-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thieno[2,3-c]ꢀ
pyridazine (6b): Yield (0.40 g, 83%), m.p. 140–141°C; IR(cm-1):ꢀ
2193 (C≡N), 1595 (C=N) cm-1;ꢀMSꢀ(m/z%): 484 (M+,ꢀ5),ꢀ458ꢀ(10),ꢀ
401 (10), 363 (10), 286 (7), 231 (100), 198 (34), 127 (18), 101
7-Cyano-6-morpholino-3,4,8-triphenylpyrido[2',3'ꢀ:ꢀ4,5]thienoꢀ
[2,3-c]pyridazineꢀ (8d): Yield (0.43 g, 82%), m.p. 82–83°C;ꢀ
IR(cm-1):2228(C≡N),1654(C=N),1341(3°-amine)cm-1;ꢀMSꢀ(m/z%):ꢀ
525ꢀ(M+, 0.4), 448 (4), 375 (20), 286 (5), 139 (8), 127 (12), 89 (100).
Anal. Calcd for C32H23N5OS: C, 73.12; H, 4.41; N, 13.33. Found: C,
73.40; H, 4.50; N, 13.60%.
1
(11), 89 (13), 77 (17); HꢀNMRꢀ(DMSOꢀ–ꢀd6)ꢀd ppm: 1.22 (t, 3H,
CH3), 3.79 (q, 2H, CH2), 7.04–7.98 (m, 15H, 3Ph). Anal. Calcd for
C30H20N4OS: C, 74.36; H, 4.16; N, 11.56. Found: C, 74.60; H, 4.30;
N, 11.80%.

JOURNAL OF CHEMICAL RESEARCH 2009 597
6-Substituted aminopyridothienopyridazine derivatives 9a–f; general
procedure
117°C as brown crystals; IR(cm-1): 3588, 3444(NH2), 3322(NH),
1611 (C=N), 1364 (3°-amine) cm-1; MS (m/z%): 472 (M+ + 1, 0.03),
383 (0.43), 286 (100), 254 (3), 230 (9), 202 (6), 190 (16), 103 (31),
87 (13), 77 (54). Anal. Calcd for C28H18N6S: C, 71.47; H, 3.86; N,
17.86. Found: C, 71.70; H, 3.90; N, 17.60%.
A mixture of 6-chloro-7-cyano-3, 4, 8-triphenylpyrido[2', 3':4, 5]
thieno[2, 3-c]pyridazine (5) (1.0 mmol) and 4-aminobenzene-
sulfonamide derivatives (15a–f) (1.0 mmol) was refluxed in benzene
(20 mL) for 5 h. The reaction mixture was cooled to room temperature
and the separated solid was filtered off, washed with water, dried, and
recrystallised from ethanol to give (9a–f).
8-Substituted 3,4-diphenylpyrimido[4',5':4,5]thieno[2,3-c]pyridazins
(16a–g) and (17a,b); general procedure
4-[(7-Cyano-3,4,8-triphenylpyrido[2',3' : 4,5]thieno[2,3-c]
pyridazin-6-yl)amino]benzenesulfonamide (9a): Yield (0.55 g, 90%),
m.p. 158–159°C; IR(cm-1): 3369, 3294 (NH, SO2NH2), 2251 (C≡N),
1658 (C=N), 1329 (SO2, asym), 1156 (SO2, sym) cm-1; MS (m/z%):
611 (M+, 2), 508 (7), 407 (100), 376 (50), 101 (47). Anal. Calcd for
C34H22N6O2S2: C, 66.87; H, 3.63; N, 13.76. Found: C, 67.10; H,
3.80; N, 13.50%.
N-Propyl-4-[(7-cyano-3,4,8-triphenylpyrido[2',3':4,5]thieno[2,3-c]
pyridazin-6-yl)amino]benzenesulfonamide (9b): Yield (0.57 g,
88%), m.p. 122–123°C; IR(cm-1): 3380, 3201 (NH, SO2NHR),
2229 (C≡N), 1670 (C=N), 1336 (SO2, asym), 1161 (SO2, sym) cm-1;
MS (m/z%): 652 (M+, 0.42), 439 (30), 366 (73), 334 (100), 58 (40);
1H NMR (DMSO – d6) d ppm: 0.6–0.8 (t, 3H, CH3), 0.95–1.51 (m,
2H, CH2CH3), 2.49–2.82 (m, 2H, NHCH2), 2.77–2.95 (t, 1H, NH),
3.48 (s, 1H, NH), 6.63–7.12 (m, 4H, Ar), 7.15–7.95 (m, 15H, 3Ph).
Anal. Calcd for C37H28N6O2S2: C, 68.08; H, 4.32; N, 12.88. Found:
C, 68.30; H, 4.20; N, 13.10%.
Amixture of 8-chloro-3, 4-diphenylpyrimido[4', 5':4, 5]thieno[2, 3-c]
pyridazin (14) (1.0 mmol) and 4-aminobenzenesulfonamide
derivatives (15a–g) and 2°- amine (diethyl amine and pyrrolidine)
(1.0 mmol) was refluxed in n-butanol (10 mL) or ethanol/THF
(10 mL 1:4 v/v) for 3 h. The reaction mixture was cooled to room
temperature. The separated solid was filtered off, washed with water,
dried and recrystallised from ethanol.
4-[(3,4-Diphenylpyrimido[4',5':4,5]thieno[2,3-c]pyridazin-8-yl)
amino]benzenesulfonamide (16a): Yield (0.43 g, 85%), m.p. 190–
191°C; IR(cm-1): 3369, 3293 (NH, SO2NH2), 1656 (C=N), 1330
(SO2, asym), 1155 (SO2, sym) cm-1; MS (m/z%): 512 (M+ + 1, 0.03),
286 (30), 242 (14), 172 (100), 155 (57), 101 (45), 91 (54), 64 (50),
76 (30). Anal. Calcd for C26H18N6O2S2: C, 61.16; H, 3.55; N, 16.46.
Found: C, 61.40; H, 3.50; N, 16.20%.
N-Propyl-4-[(3,4-diphenylpyrimido[4',5' : 4,5]thieno[2,3-c]
pyridazin-8-yl)amino]benzenesulfonamide (16b): Yield (0.50 g,
90%), m.p. 154–155°C; IR(cm-1): 3436, 3363 (NH, SO2NHR), 1596
(C=N), 1338 (SO2, asym), 1157 (SO2, sym) cm-1; MS (m/z%): 555
N-Benzyl-4-[(7-cyano-3,4,8-triphenylpyrido[2',3':4,5]thieno[2,3-c]
pyridazin-6-yl)amino]benzenesulfonamide (9c): Yield (0.60 g, 85%),
m.p. 92–93°C; IR(cm-1): 3316, 3213 (NH, SO2NHR), 2240 (C≡N),
1678 (C=N), 1313 (SO2, asym), 1153 (SO2, sym) cm-1; MS (m/z%):
702 (M+ + 1, 47), 624 (62), 598 (43), 338 (100), 286 (43), 184 (41),
1
(M+ + 2, 4), 286 (7), 242 (11), 213 (8), 170 (1), 64 (100); H NMR
(DMSO – d6) d ppm: 1.09 (t, 3H, CH3), 1.52 (m, 2H, CH2), 2.78 (s,
1H, NH), 3.37 (m, 2H, CH2), 4.45 (t, 1H, NH), 6.26–7.32 (m, 14H,
ArH), 7.36 (s, 6-H, 1H). Anal. Calcd for C29H24N6O2S2: C, 63.02; H,
4.38; N, 15.21. Found: C, 63.30; H, 4.20; N, 15.50%.
1
169 (46); H NMR (DMSO – d6) d ppm: 3.98–4.04 (d, 2H, CH2),
2.49–2.83 (t, 1H, NH), 4.0 (s, 1H, SO2NH), 6.62–6.65 (m, 4H, Ar),
7.22–7.94 (m, 20H, 4Ph). Anal. Calcd for C41H28N6O2S2: C, 70.26;
H, 4.03; N, 11.99. Found: C, 70.00; H, 4.20; N, 11.70%.
N-(4-Methylphenyl)-4-[(7-cyano-3,4,8-triphenylpyrido[2',3':4,5]
thieno[2,3-c]pyridazin-6-yl)amino]benzenesulfonamide (9d): Yield
(0.56 g, 80%), m.p. 142–143°C; IR(cm-1): 3313, 3202 (NH,
SO2NHR), 2233 (C≡N), 1681(C=N), 1324 (SO2, asym), 1151 (SO2,
sym) cm-1; MS (m/z%): 700 (M+, 0.01), 439 (2), 375 (19), 359 (100),
101 (12). Anal. Calcd for C41H28N6O2S2: C, 70.26; H, 4.03; N, 11.99.
Found: C, 70.50; H, 3.90; N, 12.30%.
N-Benzyl-4-[(3,4-diphenylpyrimido[4',5' : 4,5]thieno[2,3-c]
pyridazin-8-yl)amino]benzenesulfonamide (16c): Yield (0.49 g,
82%), m.p. 133–134°C; IR(cm-1): 3369, 3261 (NH, SO2NHR), 1596
(C=N), 1361 (SO2, asym), 1157 (SO2, sym) cm-1; MS (m/z%): 600
(M+, 0.10), 532 (0.1), 300 (1), 254 (1), 101 (1), 77 (100), 53 (7); 1H
NMR (DMSO – d6) d ppm: 3.38 (t, 1H, NH), 3.88 (s, 1H, NH), 4.34
(d, 2H, CH2), 6.27–7.60 (m, 19H, ArH), 7.65(s, 6-H, 1H). Anal. Calcd
for C33H24N6O2S2: C, 65.98; H, 4.03; N, 13.99. Found: C, 65.70; H,
4.20; N, 13.70%.
N-Phenyl-4-[(3,4-diphenylpyrimido[4',5' : 4,5]thieno[2,3-c]
pyridazin-8-yl)amino]benzenesulfonamide (16d): Yield (0.50 g,
85%), m.p. 172–173°C; IR(cm-1): 3349, 3241 (NH, SO2NHR), 1594
(C=N), 1311 (SO2, asym), 1153 (SO2, sym) cm-1; MS (m/z%): 587
(M+, 0.42), 531 (4), 248 (34), 156 (68), 92 (69), 77 (26), 64 (56), 60
N-(4-Methoxyphenyl)-4-[(7-cyano-3,4,8-triphenylpyrido[2',3':4,5]
thieno[2,3-c]pyridazin-6-yl)amino]benzenesulfonamide (9e): Yield
(0.61 g, 85%), m.p. 120–121°C; IR(cm-1): 3372, 3211 (NH,
SO2NHR), 2232 (C≡N), 1670 (C=N), 1321 (SO2, asym), 1152 (SO2,
sym) cm-1; MS (m/z%): 716 (M+, 2), 627 (3), 589 (2), 439 (83), 375
1
(100); H NMR (DMSO – d6) d ppm:4.78 (s, br, 1H, NH), 5.02 (s,
1
(100), 336 (26); H NMR (DMSO – d6) d ppm: 2.50 (s, 1H, NH),
1H, NH), 6.52–7.36 (m, 19H, ArH), 9.86 (s, 6-H, 1H). Anal. Calcd
for C32H22N6O2S2: C, 65.51; H, 3.78; N, 14.33. Found: C, 65.80; H,
3.70; N, 14.60%.
2.76 (s, 1H, SO2NH), 3.62 (s, 3H, CH3), 6.51–6.78 (m, 4H, Ar),
6.93–7.09 (m, 4H, Ar-SO2), 7.11–7.96 (m, 15H, 3Ph). Anal. Calcd
for C41H28N6O3S2: C, 68.70; H, 3.94; N, 11.73. Found: C, 68.40; H,
3.80; N, 11.50%.
N-(4-Methoxyphenyl)-4-[(3,4-diphenylpyrimido[4',5':4,5]thieno
[2,3-c]pyridazin-8-yl)amino]benzenesulfonamide
(16e):
Yield
N-(4-Nitrophenyl)-4-[(7-cyano-3,4,8-triphenylpyrido[2',3':4,5]
thieno[2,3-c]pyridazin-6-yl)amino]benzenesulfonamide (9f): Yield
(0.47 g, 65%), m.p. 146–147°C; IR(cm-1): 3315, 3199 (NH,
SO2NHR), 2222 (C≡N), 1675 (C=N), 1523 (NO2, asym), 1392 (NO2,
sym), 1340 (SO2, asym), 1153 (SO2, sym) cm-1; MS (m/z%): 732
(M+, 0.1), 629 (3), 446 (5), 357 (34), 102 (61), 90 (54), 64 (43), 77
(100). Anal. Calcd for C40H25N7O4S2: C, 65.65; H, 3.44; N, 13.40.
Found: C, 65.90; H, 3.30; N, 13.10%.
7-Cyano-3,4,8-triphenylpyrido[2',3':4,5]thieno[2,3-c]pyridazin-
6(5H)-thione (10): A mixture of 6-chloro-7-cyano-3, 4, 8-triphenyl-
pyrido[2', 3':4, 5]thieno[2, 3-c]pyridazin (5) (1 g) and thiourea
(1 g) in ethyl alcohol (20 mL) was refluxed for 2 h. The solvent was
evaporated and the residue was dissolved in 2.5N sodium hydroxide
solution followed by refluxing for half an hour. The solution was
filtered while on hot, allowed to cool and acidified with hydrochloric
acid (pH 6). The separated solid product was filtered off, washed with
water, dried and recrystallised from ethanol to give 0.85 g (85%) of
(10), m.p. 145–146°C as yellow crystals; IR(cm-1): 2225 (C≡N),
1647 (C=N), 697 (strong band, CــS) cm-1; MS (m/z%): 473 (M+, 1),
265 (2), 254 (4), 187 (1), 173 (2), 140 (1), 128 (4), 110 (2), 98 (3), 90
(1), 77 (3), 64 (100). Anal. Calcd for C28H16N4S2: C, 71.16; H, 3.41;
N, 11.86; Found: C, 71.40; H, 3.50; N, 11.60%.
(0.50 g, 80%), m.p. 176–177°C; IR(cm-1): 3282, 3264 (NH,
SO2NHR), 1594 (C=N), 1308 (SO2, asym), 1149 (SO2, sym) cm-1;
MS (m/z%): 616 (M+, 0), 277 (33), 186 (0.10), 170 (0.30), 122 (100),
107 (7), 91 (8), 64 (13), 52 (7); 1H NMR (DMSO – d6) d ppm: 3.66
(s, 3H, CH3), 5.73 (s, br, 1H, NH), 6.50–7.36 (m, 18H, ArH), 9.46
(s, 6-H, 1H). Anal. Calcd for C33H24N6O3S2: C, 64.27; H, 3.92; N,
13.63. Found: C, 64.00; H, 3.80; N, 13.90%.
N-(4-Chlorophenyl)-4-[(3,4-diphenylpyrimido[4',5':4,5]thieno
[2,3-c]pyridazin-8-yl)amino]benzenesulfonamide
(16f):
Yield
(0.47 g, 75%), m.p. 168–169°C; IR(cm-1): 3345, 3056 (NH,
SO2NHR), 1594 (C=N), 1317 (SO2, asym), 1153 (SO2, sym) cm-1;
MS (m/z%): 621 (M+, 0.1), 623 (M+ + 2, 0.1), 281 (21), 155 (67), 126
(45), 64 (34), 91 (46), 77 (100). Anal. Calcd for C32H21ClN6O2S2: C,
61.88; H, 3.41; N, 13.53. Found: C, 61.60; H, 3.50; N, 13.30%.
N-(4-Nitrophenyl)-4-[(3,4-diphenylpyrimido[4',5' : 4,5]thieno
[2,3-c]pyridazin-8-yl)amino]benzenesulfonamide
(16g):
Yield
(0.44 g, 70%), m.p. 200–201°C; IR(cm-1): 3390, 3100 (NH,
SO2NHR), 1594 (C=N), 1527 (NO2, asym), 1400 (NO2, sym), 1344
(SO2, asym), 1157 (SO2, sym) cm-1; MS (m/z%): 633 (M+ + 1, 0.1),
478 (0.60), 346 (6), 210 (4), 201 (2), 170 (4), 146 (2), 103 (100), 85
(3), 69 (11), 56 (11). Anal. Calcd for C32H21N7O4S2: C, 60.84; H,
3.35; N, 15.52. Found: C, 61.10; H, 3.20; N, 15.80%.
3-Amino-4,8,9-triphenyl-1H-pyrazolo[3',4':2,3]pyrido[5',6':5,4]
thieno[2,3-c]pyridazin (11): A mixture of compound (5) (0.48 g,
1.0 mmol) and hydrazine hydrate (0.05 g, 99%, 1.0 mmol) in
n-butanol (10 mL) was refluxed for 3 h. The solvent was removed
under reduced pressure. The solid product was collected and
recrystallised from ethanol to give 0.40 g (76%) of (11), m.p. 116–
8-Diethylamino-3,4-diphenylpyrimido[4',5' : 4,5]thieno[2,3-c]
pyridazin (17a): Yield (0.33 g, 80%), m.p. 146–147°C; IR(cm-1):
1598 (C=N), 1375 (3°-amine) cm-1; MS (m/z%): 411 (M+, 8), 382
(10), 339 (4), 300 (29), 289 (91), 237 (11), 127 (16), 98 (26), 72 (42),
58 (100); 1H NMR (DMSO – d6) d ppm: 1.18 (t, 3H, CH2CH3), 2.84
(q, 2H, CH2CH3), 6.91–7.29 (m, 10H, 2Ph), 7.40 (s, 6-H, 1H). Anal.

598 JOURNAL OF CHEMICAL RESEARCH 2009
Calcd for C24H21N5S: C, 70.04; H, 5.14; N, 17.02. Found: C, 69.80;
H, 5.00; N, 17.30%.
References
1
J. Sauer, Comprehensive, heterocyclic chemistry II; Pergamon, London,
3,4-Diphenyl-8-(pyrrolidin-1-yl)pyrimido[4',5':4,5]thieno[2,3-c]
pyridazin (17b): Yield (0.31 g, 75%), m.p. 300–302°C; IR(cm-1):
1590 (C=N), 1378 (3°-amine) cm-1; MS (m/z%): 409 (M+, 23), 339
(3), 327 (11), 300 (38), 286 (5), 173 (4), 159 (2), 146 (100), 132 (4),
1996, Vol. 6; pp 901.
2
J.A. Tucker, D.A. Allwine, K.C. Grega, M.R. Barbachyn, J.L. Klock,
J.L. Adamski, S.J. Brickner, D.K. Hulchinson, C.W. Ford, G.E. Zurenko,
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3723.
G.P. Ellis, Synthesis of fused feterocycles; John Wiley and Sons Inc.:
New York, 1987, pp. 226.
Z.X. Yu, Q. Dang and Y.D. Wu, J. Org. Chem., 2001, 66, 6029.
A. Volonterio, L. Moisan and J. Rebec, J. Org. Lett., 2007, 9, 3733.
R.S. Vartanyan, Zh. V. Kazaryan, M.A. Sheriranyan, A.S. Agaranyan and
N.O. Stepanyan, Khim, Farm., Zh., 1996, 30, 29.
F. El-Mariah, E. Nassar, M. Hosny and A. Deeb, Phosphorus, Sulfur,
Silicon, 2009, 184, 92.
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A. Deeb, A. Essawy, F. Yasine and R. Fikry, Z. Naturforsch, 1991, 46b,
835.
1
109 (7), 96 (13); H NMR (DMSO – d6) d ppm: 1.28 (t, 4H, 2CH2,
3
b-pyrrolidine protons), 1.81 (t, 4H, 2CH2, a-pyrrolidine protons),
7.07–7.26 (m, 10H, 2Ph), 7.70 (s, 6-H, 1H). Anal. Calcd for
C24H19N5S: C, 70.39; H, 4.68; N, 17.10. Found: C, 70.60; H, 4.50;
N, 16.80%.
4
5
6
7
The author acknowledges the help of Quality Control and
Propagation of Plants, Department of Botany, Faculty of
Girls, Ain Shams University for carrying out the antimicrobial
activity.
8
9
10 J.M. Quintela, M.C. Veiga, R. Alvarez-Sarandes, L. González and
C. Peinador, Monatsh. Chem., 1996, 127, 1037.
11 Vogel's textbook of practical organic chemistry, Longman Group Limited,
London, 1980, 4th edn., pp. 651.
12 A.W. Bauer, W.W. Mkriby, J.C. Sherris and M. Turck, Am. J. Clin.
Pathol., 1966, 45, 493.
Received 23 June 2009; accepted 11 August 2009
Paper 09/0652 doi: 10.3184/030823409X12508790019612
Published online: 8 October 2009